The primary objective of the study is to evaluate the safety of Recombinant Coagulation Factor VIII Fc Fusion Protein (rFVIIIFc) in previously treated pediatric subjects with hemophilia A. Secondary objectives of this study in this study population are as follows: to evaluate the efficacy of rFVIIIFc for prevention and treatment of bleeding episodes; to evaluate and assess the pharmacokinetics (PK) of rFVIIIFc; and to evaluate rFVIIIFc consumption for prevention and treatment of bleeding episodes.

An Open-Label, Multicenter Evaluation of Safety, Pharmacokinetics, and Efficacy of Recombinant Coagulation Factor VIII Fc Fusion Protein, BIIB031, in the Prevention and Treatment of Bleeding Episodes in Pediatric Subjects With Hemophilia A

Occurrence of FVIII Inhibitor Development [ Time Frame: Up to Week 26 +/- 7 days, or up to 50 exposure days (EDs) if reached prior to Week 26 ] [ Designated as safety issue: Yes ]

An inhibitor test result ≥0.6 Bethesda units (BU)/mL, confirmed on 2 separate samples drawn 2 to 4 weeks apart, was considered positive. Both tests were to be performed by the central laboratory using the Nijmegen-modified Bethesda Assay. Incidences were summarized for any positive inhibitor for participants with ≥50 EDs to rFVIIIFc. In addition, the incidence for all participants, regardless of their EDs to rFVIIIFc, was also summarized. An exact 95% CI for the proportion of participants with a confirmed inhibitor was calculated using the Clopper-Pearson exact method for a binomial proportion.

Secondary Outcome Measures:

Annualized Bleeding Rate [ Time Frame: Up to Week 26 +/- 7 days (efficacy period as defined in description) ] [ Designated as safety issue: No ]

Annualized bleeding rate = (number of bleeding episodes during the efficacy period / total number of days during the efficacy period)*365.25. The efficacy period begins with the first prophylactic dose of rFVIIIFc and ends with the last dose (for prophylaxis or a bleed). Surgery/rehabilitation periods and PK evaluation periods are not included in the efficacy period. A bleeding episode started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. Any injection to treat the bleeding episode taken more than 72 hours after the preceding one was considered the first injection to treat a new bleeding episode at the same location. Any bleeding at a different location was considered a separate bleeding episode, regardless of time from last injection.

Annualized Joint Bleeding Rate (Spontaneous) [ Time Frame: Up to Week 26 +/- 7 days (efficacy period as defined in description) ] [ Designated as safety issue: No ]

Annualized bleeding rate for spontaneous joint bleed=(number of bleeding episodes meeting those criteria during the efficacy period/total number of days during the efficacy period)*365.25. The efficacy period begins with the first prophylactic dose of rFVIIIFc and ends with the last dose (for prophylaxis or a bleed). Surgery/rehabilitation periods and PK evaluation periods are not included in the efficacy period. A bleeding episode started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. Any injection to treat the bleeding episode taken more than 72 hours after the preceding one was considered the first injection to treat a new bleeding episode at the same location. Any bleeding at a different location was considered a separate bleeding episode, regardless of time from last inject

Participant Assessment of Response to Injections to Treat a Bleeding Episode [ Time Frame: Up to Week 26 +/- 7 days ] [ Designated as safety issue: No ]

Participant's assessment (provided by the caregiver) of the response to the first rFVIIIFc injection for each bleeding episode. Percentages were based on the number of first injections for which a response was provided, using the following 4-point scale: excellent=abrupt pain relief and/or improvement in signs of bleeding within approximately 8 hours after the initial injection; good=definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after a single injection, but possibly requiring more than one injection after 24 to 48 hours for complete resolution; moderate=probable or slight beneficial effect within approximately 8 hours after the initial injection and requiring more than one injection; no response=no improvement, or condition worsened, within approximately 8 hours after the initial injection.

Physician's Global Assessment of the Participant's Response to His rFVIIIFc Regimen [ Time Frame: Up to Week 26 +/- 7 days ] [ Designated as safety issue: No ]

Investigators assessed each participant's response to his rFVIIIFc regimen using a 4-point scale: excellent=bleeding episodes responded to ≤ the usual number of injections or ≤ the usual dose of rFVIIIFc or the rate of breakthrough bleeding during prophylaxis was ≤ that usually observed; effective=most bleeding episodes responded to the same number of injections and dose, but some required more injections or higher doses, or there was a minor increase in the rate of breakthrough bleeding; partially effective=bleeding episodes most often required more injections and/or higher doses than expected, or adequate breakthrough bleeding prevention during prophylaxis required more frequent injections and/or higher doses; ineffective=routine failure to control hemostasis, or hemostatic control required additional agents. Percentages are based on the total number of responses; multiple responses per participant are counted.

Annualized rFVIIIFc Consumption Per Participant [ Time Frame: Up to Week 26 +/- 7 days (efficacy period as defined in description) ] [ Designated as safety issue: No ]

Consumption is calculated for the efficacy period. The efficacy period begins with the first prophylactic dose of rFVIIIFc and ends with the last dose (for prophylaxis or a bleed). Surgery/rehabilitation periods and PK evaluation periods are not included in the efficacy period. Annualized consumption = (total IU/kg of study treatment received during the efficacy period / total number of days during the efficacy period)*365.25. Consumption was calculated overall for all participants and for the last 3 months (91 days) on study, counted backwards from the end of the efficacy period, for participants with at least 24 weeks on study.

Number of Days From Last Treatment Injection to a Spontaneous Bleeding Episode [ Time Frame: Up to Week 26 +/- 7 days (efficacy period as defined in description) ] [ Designated as safety issue: No ]

The number of days from the last prophylaxis injection to the onset of a new spontaneous bleeding episode, analyzed across all evaluable bleeding episodes per participant and per episode, based on the efficacy period. Evaluable bleeding episodes are those for which both a date and time are available for both the onset of the bleeding episode and the previous prophylactic injection. The efficacy period begins with the first prophylactic dose of rFVIIIFc and ends with the last dose (for prophylaxis or a bleed). Surgery/rehabilitation periods and PK evaluation periods are not included in the efficacy period. For 'Per participant' values, the number of days from the last prophylactic injection to a spontaneous bleeding episode is averaged across all evaluable spontaneous bleeding episodes per participant.

Number of Injections Required for Resolution of a Bleeding Episode [ Time Frame: Up to Week 26 +/- 7 days (efficacy period as defined in description) ] [ Designated as safety issue: No ]

The number of injections required to resolve a bleeding episode per participant and per episode, based on the efficacy period. The efficacy period begins with the first prophylactic dose of rFVIIIFc and ends with the last dose (for prophylaxis or a bleed). Surgery/rehabilitation periods and PK evaluation periods are not included in the efficacy period. All injections given from the initial sign of a bleed, until the last date/time within the bleed window are counted. The resolution of a bleed is defined as no sign of bleeding following injection for the bleed. For 'Per participant' values, the number of injections required to resolve each bleed is averaged across all bleeding episodes per participant.

Total Dose Required for Resolution of a Bleeding Episode [ Time Frame: Up to Week 26 +/- 7 days (efficacy period as defined in description) ] [ Designated as safety issue: No ]

The total dose required to resolve a bleeding episode per participant and per episode, based on the efficacy period. The efficacy period begins with the first prophylactic dose of rFVIIIFc and ends with the last dose (for prophylaxis or a bleed). Surgery/rehabilitation periods and PK evaluation periods are not included in the efficacy period. For 'Per bleeding episode' values, for each bleeding episode, the total dose is the sum of the doses (IU/kg) administered across all injections given to treat that bleeding episode. For 'Per participant' values, the total dose (IU/kg) used to resolve each bleed is averaged across all bleeding episodes per participant.

Maximum plasma activity during a dosing interval for participants in the PK subgroup. The values for Cmax were adjusted to the nominal dose of 50 IU/kg. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Maximum plasma activity during a dosing interval for participants in the PK subgroup. The values for Cmax were adjusted to the nominal dose of 50 IU/kg. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Time required for the activity of the drug to reach half of its original value for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Time required for the activity of the drug to reach half of its original value for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Rate at which the body removes the drug, measured as the volume of the plasma cleared of drug per unit time per unit weight for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Rate at which the body removes the drug, measured as the volume of the plasma cleared of drug per unit time per unit weight for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Dose normalized area under the FVIII activity-time curve for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Dose normalized area under the FVIII activity-time curve for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

The average time that a drug molecule is present in the systemic circulation for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

The average time that a drug molecule is present in the systemic circulation for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

The rise in FVIII activity in IU/dL per unit dose administered in IU/kg for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

The rise in FVIII activity in IU/dL per unit dose administered in IU/kg for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Time at which maximum activity (Cmax) is observed for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Time at which maximum activity (Cmax) is observed for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

First order rate constant associated with the terminal portion of the curve (lambda z) for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

First order rate constant associated with the terminal portion of the curve (lambda z) for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Volume of distribution estimated from the terminal phase for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Volume of distribution estimated from the terminal phase for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Dose-normalized area under the FVIII activity-time curve to the last measurable timepoint for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Dose-normalized area under the FVIII activity-time curve to the last measurable timepoint for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Dose normalized area under the FVIII activity-time curve to infinity for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Dose normalized area under the FVIII activity-time curve to infinity for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Percentage of AUCinf extrapolated from the last data point to infinity for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

Percentage of AUCinf extrapolated from the last data point to infinity for participants in the PK subgroup. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.

PK subgroup: After a Washout Period of ≥72 hours, at the Baseline Visit (28±7 days prior to Day 1), participants receive a single IV injection of prestudy FVIII over 5 (±2) minutes at a dose of 50 IU/kg, rounded up to the nearest 250 IU increment, for a PK assessment. Following a second Washout Period of ≥72 hours, participants receive a single IV injection of rFVIIIFc over 5 (±2) minutes at a dose of 50 IU/kg for PK assessment. The first prophylactic dose of rFVIIIFc is administered at a starting dose of 25 IU/kg IV injection on Day 1 and 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated.

Non-PK subgroup: On Day 1, a first prophylactic dose of rFVIIIFc of 25 IU/kg IV injection is given, followed by a dose of 50 IU/kg on Day 4. Dose increases to a maximum of 80 IU/kg, and frequency of administration to a minimum interval of once every 2 days, are allowed as indicated.

Drug: BIIB031 (rFVIIIFc)

Vials of rFVIIIFc were combined as needed, based on the actual labeled potency to achieve the participant's calculated dose. Partial vial use was allowed, in order to achieve the calculated dose.

Other Names:

ELOCTATE

efmoroctocog alfa

antihemophilic factor (recombinant), Fc fusion protein

recombinant coagulation factor VIII Fc fusion protein

Drug: FVIII (PK subgroup only)

Baseline prestudy FVIII dosing in participants who enter the PK subgroup. Vials of prestudy FVIII were combined as needed, based on the nominal labeled potency (e.g., 250 IU, 500 IU, and 1000 IU), to achieve the participant's calculated dose.

Detailed Description:

Previously treated pediatric participants will be treated with a prophylactic regimen of rFVIIIFc. PK analysis of pre-study factor VIII (FVIII) and rFVIIIFc will be performed in a sub-group of the study participants prior to commencement of prophylactic treatment. After these PK results are available, remaining participants have the option of proceeding directly to prophylactic treatment. After completing the end of study assessments, eligible participants would be able to continue treatment in Study 8HA01EXT.

Eligibility

Ages Eligible for Study:

up to 11 Years

Genders Eligible for Study:

Male

Accepts Healthy Volunteers:

No

Criteria

Key Inclusion Criteria:

Severe hemophilia A defined as <1 IU/dL (<1%) endogenous FVIII

Male <12 years of age and weight ≥13 kg

History of at least 50 documented prior exposure days to FVIII

No current, or history of, inhibitor development to FVIII

Key Exclusion Criteria:

Other coagulation disorders in addition to Hemophilia A

History of anaphylaxis associated with any FVIII or IV immunoglobulin administration

NOTE: Other protocol-defined Inclusion/Exclusion criteria may apply.

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01458106